Benzothiophene derivatives

ABSTRACT

The invention relates to compounds of the general formula I ##STR1## wherein R 1  represents one up to and including four, the same or different substituents selected from alkyl(1-6 C), alkoxy(1-6 C), hydroxy, halogen, NO 2  CF 3  or the group --NR 5  R 6 , whereby two substituents taken together may also represent a methylene-dioxy group, 
     X represents nitrogen or the group ##STR2## n has the value 0, 1 or 2, R 3  represents one of the moieties: ##STR3##  the latter meaning of R 3  (amide) only under the condition that for X is nitrogen the meaning of R 1  is limited to substituents selected from hydroxy, alkoxy(1-6 C) and methylenedioxy, and R 4 , R 5  and R 6  represent hydrogen or alkyl(1-6 C), and pharmaceutically acceptable salts thereof, suitable in the treatment of heart failure.

The invention relates to compounds of the general formula I ##STR4##wherein R₁ represents one up to and including four, the same ordifferent substituents selected from alkyl(1-6 C), alkoxy(1-6 C),hydroxy, halogen, NO₂, CF₃ or the group --NR₅ R₆, whereby twosubstituents taken together may also represent a methylene-dioxy group,

X represents nitrogen or the group ##STR5## n has the value 0, 1 or 2,R₃ represents one of the moieties: ##STR6## the latter meaning of R₃(amide) only under the condition that for X is nitrogen the meaning ofR₁ is limited to substituents selected from hydroxy, alkoxy(1-6 C) andmethylenedioxy, and R₄, R₅ and R₆ represent hydrogen or alkyl(1-6 C) andpharmaceutically acceptable salts thereof.

The compounds according to the invention have a cardiotonic activity andmore particularly they show a very potent increase of the force andenergy of the heart-muscular contractions (postive inotropic effect).

The compounds of the invention may be prepared by any method known forthe preparation of analogous compounds.

A very suitable starting product for the preparation of the compounds Iis a compound of the formula II ##STR7## wherein R₁, n and X have theaforesaid meanings.

Compounds of the invention in which R₃ represents the moiety ##STR8##may for example be prepared by reacting the compound of formula II or anacid halide or anhydride thereof with an amine of the formula III orhydroxylamine of the formula V: ##STR9## R₅ and R₆ have the aforesaidmeaning, or a reactive derivative thereof, in which the hydrogen atom isreplaced by a more reactive moiety, such as an alkali metal.

Compounds of the formula I, in which R₃ represents the moiety ##STR10##may also be prepared by reacting a compound of formula II or an acidhalide or anhydride thereof with an alkali metal azide, followed byreduction of the resulting azide.

Compounds of the invention in which R₃ represents a ##STR11## moietymay, for example, be prepared from a nitrile of the general formula IV:##STR12## in which R₁, X and n have the meanings assigned before byreacting the said nitrile in the usual manner with a compound of theformula V: ##STR13## wherein R₅ has the aforesaid meanings, or areactive derivative thereof, in which hydrogen (at the nitrogen atom)has been replaced by a more reactive moiety, such as an alkali metal.

The nitrile of formula IV may be prepared in the usual manner from thecorresponding carboxylic acid of formula II by converting the carboxylicacid into the corresponding carboxamide followed by dehydration of thecarboxamide.

Compounds of the invention, in which R₃ represents a--C═N--NH--C(═NH)NH₂ moiety, may most conveniently be prepared from analdehyde of the formula: ##STR14## by condensation of this compound (VI)with amino guanidine or a salt thereof.

The aldehyde of formula VI can be prepared in various manners. Forexample the aldehyde may be manufactured by reducing the carboxylic acidof formula II in a well known manner.

Another convenient synthesis for preparing the aldehyde consists of amild reduction of the corresponding nitrile of formula II, e.g. with theaid of a metal hydride such as diisobutylaluminiumhydride.

The starting product of general formula II may be prepared by knownmethods. The attached flow sheet shows the preparation of a compound offormula II, wherein n=0. Chain length extension to n=1 and n=2 can beobtained by converting the carboxylic acid II (n=0) into thecorresponding aldehyde (n=0) and reacting said aldehyde with theappropriate phosphonate-ylid using reaction conditions well known incarrying out the Wittig reaction.

Appropriate phosphonate ylids are, for example, cyanomethylenetriphenylphosphorane, carboxymethylene triphenylphosphorane andcorresponding (alkyl)esters, and 3-cyano propen(2)-ylidenetriphenylphosphorane. If necessary, the nitrile--obtained through thisWittig reaction--can be converted into the corresponding amide orcarboxylic acid.

Preferably most substituents at the benzo-ring (see R₁) are alreadypresent in one of the starting products. Nevertheless it is very wellpossible to convert a substituent R₁ into another substituent R₁ afterthe above mentioned condensation reactions.

Thus, one or more hydroxy groups (R₁) may be converted into thecorresponding alkoxy groups or halogen in the usual manner. Furthermoretwo hydroxy groups may be converted into one methylene-dioxy group andan alkoxy group may be hydrolysed to the corresponding hydroxy group.

The compounds according to the general formula I may be converted into apharmaceutically acceptable salt.

The compounds of formula I which have an alkaline character may beobtained as the free base or as an acid addition salt. If required,however, the free base I can be prepared from the salt, for example byreaction with an alkaline compound or by means of an ion exchanger,whilst the free base I can be converted in a simple manner into an acidaddition salt.

Pharmaceutically acceptable acid addition salts are derived from acids,such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid,propionic acid, glycolic acid, maleic acid, fumaric acid, malonic acid,succinic acid, tartaric acid, lactic acid, citric acid, ascorbic acid,salicylic acid, benzoic acid and methanesulphonic acid.

Compounds I having an acidic nature may be converted into a metal salt,preferably an alkali metal salt such as the sodium salt.

By the term "alkyl(1-6 C)" as used in the definitions of R₁, R₄, R₅ andR₆ is meant a saturated hydrocarbon with 1 to 6 carbon atoms, andpreferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert. butyl, pentyl and isopentyl.

An alkoxy(1-6 C) group is an alkyloxy group, in which the term alkyl hasa similar meaning as above.

By halogen in the definition of R₁ is preferably meant iodine, bromine,chlorine and fluorine. The most preferred halogens are chlorine andbromine.

The said compounds in accordance with the invention can be administeredeither orally, locally or parenterally, preferably in a daily dosebetween 0.01 and 50 mg/kg body weight. For this purpose the compoundsare processed in a form suitable for oral, local or parenteraladministration, for example a tablet, pill, capsule, solution,suspension, emulsion, paste or spray. The oral form is the mostpreferred form of administration.

The most potent inotropic compounds are found amongst those compounds offormula I in which at least two substituents R₁ are present selectedfrom hydroxy or alkoxy or in which at least one methylene-dioxy group(R₁) is present, whereby the dimethoxy or methoxy-hydroxy substitutionpattern is most preferred.

Preferred compounds of formula I are moreover those compounds I in whichX is --CH═.

The position of the double bond between nitrogen and carbon in some ofthe moieties defined by R₃ of formula I cannot be clearly specified,because an equilibrium will prevail between: ##STR15##

The preferred R₃ moiety in the compounds of the invention is the amidemoiety and especially the N-hydroxy-(carbox)imidamide moiety.

The preferred value of n is 0 or 1.

EXAMPLE 1 5,6-Dimethoxy-benzo[b]thiphene-2-carboxamide

A mixture of 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (68.8 g),dry toluene (350 ml), thionyl chloride (126 ml) and pyridine (1.75 ml)was stirred and heated at reflux for 4 hours. The resultant mixture wascooled, evaporated to dryness under vacuum and the residue was purgedwith dry toluene (3×250 ml). The resulting crude acid chloride wassuspended in dioxan (160 ml) then cooled in an ice bath and treated inone portion with concentrated ammonium hydroxide solution (33% w/w, 900ml). This gave a suspension of brown solid which was stirred for twohours then filtered, washed with water and dried under vacuum overcalcium chloride at 60° C. to give5,6-dimethoxybenzo[b]thiophene-2-carboxamide (62.5 g), m.p. 211°-213° C.

EXAMPLE 2 A. 5,6-Dimethoxy-benzo[b]thiophene-2-carbonitrile

5,6-Dimethoxy-benzo[b]thiophene-2-carboxamide (65 g) was suspended inpyridine (325 ml). The solution was cooled to 0° C. and treated dropwisewith trifluoro acetic anhydride (185 ml) whilst maintaining the internalreaction temperature below 10° C. The mixture was then stirred at roomtemperature for 30 min. then cooled and treated dropwise with water (170ml) whilst maintaining the internal temperature below 30° C. Thereaction mixture was diluted with more water (800 ml), stirred and thebrown solid was filtered and dried under vacuum over calcium chloride at60° C. Recrystallisation from acetone/ether afforded5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile as a white solid (47 g),m.p. 125° C.

B. N-Hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide

Sodium metal (1.86 g) was cut into small pieces and added to a stirredmethanol solution (30 ml) under an atmosphere of nitrogen. When all thesodium had dissolved the hot solution was treated with a warm solutionof hydroxylamine hydrochloride (5.65 g) in methanol (40 ml). After 1 h.the white suspension of sodium chloride was filtered off and thefiltrate was added to 5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile(6.0 g). The solution was stirred at 50° C. for 3 hours then cooled,diluted with water (400 ml), stirred and the white solid filtered anddried to giveN-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide (6.74 g),m.p. 216°-219° C. (decomp.).

The free base was dissolved in methanol (120 ml), stirred, and thesolution was saturated with hydrogen chloride gas. After 5 min. thesolution was concentrated, diluted with ether and the white solid wasfiltered. Recrystallisation from methanol:ether (1:2) afforded pureN-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamidehydrochloride (6.8 g), m.p. 203°-210° C. Melting point mesylate salt:211°-212° C.

EXAMPLE 3 A. 5,6-Dihydroxy-benzo[b]thiophene-2-carbonitrile

5,6-Dimethoxy-benzo[b]thiophene-2-carbonitrile (9.0 g) was dissolved indichloromethane (135 ml) and the solution was stirred and cooled to -70°C. and treated at a rapid dropwise rate with a cold solution of borontribromide (19.5 ml) in dichloromethane (60 ml). The resultantsuspension was stirred at room temperature for 1 h. then poured intoice-cold water (1000 ml). The light coloured solid was filtered, dried,dissolved in acetone:hexane (1:1) then eluted through coarse silica(0.2-0.5 mm, Merck, 50 g) in acetone:hexane (1:1). The appropriatefractions were combined, evaporated to dryness and crystallised fromacetone/n-hexane to give 5,6-dihydroxy-benzo[b]thiophene-2-carbonitrile(7.5 g), m.p. 229°-230° C.

B. N-5,6-Trihydroxy-benzo[b]thiophene-2-carboximidamide hydrochloride

Using the procedure described in Example 2B,5,6-dihydroxy-benzo[b]thiophene-2-carbonitrile was converted intoN-5,6-trihydroxy-benzo[b]thiophene-2-carboximidamide hydrochloride.

Free base, m.p. 188°-190° C. (decomp.).

Hydrochloride, m.p. 200°-205° C. (decomp.).

EXAMPLE 4 A. Thieno[2,3-f]-1,3-benzodioxole-6-carbonitrile

A mixture of powdered potassium hydroxide (12.36 g) anddimethylsulphoxide (100 ml) was stirred at room temperature for 5 min.then treated with 5,6 -dihydroxy-benzo[b]thiophene-2-carbonitrile (5.26g). After 1 minute di-iodomethane (4.4 ml) was added and the suspensionwas stirred at room temperature for 75 minutes, then more di-iodomethane(2.2 ml) was added. After a further 30 minutes the reaction was pouredinto water (500 ml) and extracted with ethyl acetate (2×100 ml). Theorganic extracts were combined, washed with 2MHCl and saturated brine,then dried and evaporated to give a brown crystalline residue. The crudeproduct was suspended in hot dichloromethane (200 ml), filtered, and thefiltrate was passed through a column of silica gel (0.2-0.5 mm, Merck,25 g). The appropriate fractions were combined and evaporated to drynessto give a white solid (3.4 g). Crystallisation from acetone/etherafforded pure thieno[2,3-f]-1,3-benzodioxole-6-carbonitrile, m.p.179°-180° C.

B. N-Hydroxy-thieno[2,3-f]-1,3-benzodioxole-6-carboximidamidehydrochloride

Using the method described in Example 2Bthieno[2,3-f]-1,3-benzodioxole-6-carbonitrile was converted intoN-hydroxy-thieno[2,3-f]-1,3-benzodioxole-6-carboximidamidehydrochloride.

Free base; m.p. 229°-231° C. (decomp.).

Hydrochloride, m.p. 200°-203° C. (decomp.).

EXAMPLE 5N-Hydroxy-5,6-dimethoxy-N-methyl-benzo[b]thiophene-2-carboximidamidehydrochloride

Sodium metal (0.40 g) was cut into small pieces and added to a stirredsolution of methanol (30 ml) under an atmosphere of nitrogen. When allthe sodium had dissolved the solution was treated with a solution ofN-methylhydroxylamine HCl (1.45 g) in methanol (30 ml). After 30 minutesthe white suspension of sodium chloride was filtered off and thefiltrate was added to 5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile(4.0 g). The resultant solution was stirred and heated at reflux for 5hours then evaporated to dryness. The residue was chromatographedthrough a column of course silica (0.2-0.5 mm, Merck, 150 g) indichloromethane:methanol (85:15 v/v). The appropriate fractions werecombined and evaporated to dryness to giveN-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide as a whitesolid (3.6 g). The free base was dissolved in ethyl alcohol (25 ml) anddichloromethane (25 ml) then treated with a solution of dry ether (200ml) saturated with HCl gas. The precipitated yellow solid was filteredand recrystallised from ethyl alcohol to giveN-hydroxy-5,6-dimethoxy-N-methyl-benzo[b]thiophene-2-carboximidamidehydrochloride (2.9 g), m.p. 237°-241° C. (decomp.).

EXAMPLE 6 A. 5,6-Dimethoxy-benzo[b]thiophene-2-carboxaldehyde

5,6-Dimethoxy-benzo[b]thiophene-2-carbonitrile (2.0 g) was suspended indry toluene (40 ml) under an atmosphere of nitrogen. The reactionmixture was cooled to -5° C. and treated dropwise with a solution ofdiisobutylaluminium hydride in toluene (1.5M, 13 ml). After 30 minutesthe solution was treated with methanol (5 ml) then poured intohydrochloric acid (1M, 200 ml) and stirred for 15 minutes. The resultantsolution was extracted into dichloromethane (4×100 ml) then the organicextracts were combined, washed with brine, dried over magnesium sulphateand evaporated to dryness. The orange residue (1.6 g) was crystallisedfrom dichloromethane:ether to give5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde as a white solid, m.p.155°-156° C.

B. 3-(5,6-Dimethoxy-benzo[b]thiophene-2-yl)-2-propenenitrile

Cyanomethylene-triphenylphosphorane was prepared according to the methodof S. Trippett and D. M. Walker [J.C.S., 1959, 3874-3876] and S. S.Novikov and G. A. Shvekhgeimer [C.A., 1961, 55, 13353 g].

A mixture of 5,6-dimethoxybenzo[b]thiophene-2-carboxaldehyde (8.14 g)and cyanomethylene triphenylphosphorane (22.06 g) in dry toluene (270ml) was stirred and heated to reflux for 1 hour. The reaction mixturewas then evaporated to dryness and the residue was dissolved in amixture of dichloromethane (50 ml) and toluene (50 ml) and passedthrough a column of coarse silica (0.2-0.5 mm, Merck, 600 g). The columneluted with toluene:ethyl acetate (4:1 v/v). The appropriate fractionswere combined and evaporated to dryness and the residue was crystallisedfrom dichloromethane:diethyl ether to give pure(E)-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-2-propenenitrile (7.56 g),m.p. 154°-158° C.

C.N-Hydroxy-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)prop-2-ene-imidamidehydrochloride

Using the procedure described in Example 2(E)-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-2-propenenitrile wasconverted into(E)-N-hydroxy-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-prop-2-ene-imidamidehydrochloride, m.p. 188°-198° C. (decomp.).

EXAMPLE 7 A. 4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid

2-(3,4-Dimethoxyphenyl)-1-mercapto-acrylic acid (165.0 g) (Tetrahedron,1969, 25, 2781-2785) was dissolved in dry dioxan (800 ml) and thesolution was stirred and heated at 60° C. A solution of chlorine (87 g)in carbon tetrachloride (700 ml) was then added over 30 min. After afurther 45 min. the reaction mixture was concentrated under reducedpressure and the residue was triturated with acetone. The resultant paleyellow solid was filtered and dried at 65° C. to give about a 1:1mixture of 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid and4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid. The crudeproduct (113 g) was suspended in ethanol (850 ml) and the mixture wasstirred and treated over 5 min. with hydrogen chloride gas. Theresultant suspension was refluxed for 5 hours and then evaporated todryness. The crystalline residue was purified by chromatography throughsilica (0.2-0.5 mm, Merck, 1.5 kg) in toluene:ethyl acetate 19:1. Theappropriate fractions were combined and evaporated to dryness to give4-chloro-5,6-dimethoxy-benzo[b]thiophene- 2-carboxylic acid ethyl esteras a white solid (35 g). A portion crystallised fromdichloromethane/methanol had m.p. 124°-126° C.

4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester(29.5 g) was suspended in a mixture of methanol (450 ml), water (75 ml)and potassium carbonate (20.4 g) under an atmosphere of nitrogen. Thereaction mixture was heated at reflux for 1 hour then cooled and pouredinto water (2.5 liter) containing hydrochloric acid (5M, 60 ml). Theresultant white solid was filtered and dried at 65° C. under vacuum togive 4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (26.8g). A portion crystallised from dichloromethane:methanol had, m.p.267°-270° C.

B. 4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide

Using the procedure described in Example 1,4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid was convertedinto 4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide, m.p.180°-182° C.

EXAMPLE 8 A. 4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile

Using the procedure described in Example 2A,4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide was convertedinto 4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile, m.p.159°-160° C.

B. 4-Chloro-N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamidehydrochloride

Using the procedure described in Example 2B,4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile was convertedinto4-chloro-N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamidehydrochloride, m.p. 191°-195° C.

EXAMPLE 9 A. 5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid ethylester

5,6-Dimethoxy-benzo[b]thiophene-2-carboxylic acid (10 g) was suspendedin ethanol (80 ml) and the mixture was stirred and heated at reflux for5 hours. The resultant solution was evaporated to dryness and thencrystallised from dichlolormethane:methanol to give5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester as a whitesolid (9.5 g), m.p. 84°-85° C.

B. N-Hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide

Hydroxylamine hydrochloride (5.3 g) was dissolved in warm ethanol (100ml). The solution was stirred under an atmosphere of nitrogen andtreated with a warm solution of potassium hydroxide (6.4 g) in ethanol(50 ml). After 10 min. a solution of5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (10 g) inethanol (250 ml) was added and the resultant mixture was allowed tostand at room temperature for 72 hours. The resultant suspension wasfiltered to remove the precipitated potassium chloride and the filtratewas evaporated to dryness. The resultant yellow residue was dissolved inwater (250 ml), filtered and the filtrate was acidified with 5Mhydrochloric acid. The precipitated product was filtered and dried at65° C. under vacuum to giveN-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide (8.3 g). Aportion crystallised from acetone had a melting point: 179°-180° C.

C. N-Hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide sodium saltmonohydrate

N-Hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboxamide (2.5 g) wasadded to a stirred solution of sodium metal (0.227 g) in methanol (55ml). After 15 min. the solution was evaporated to dryness and theresidue crystallised from methanol:ether to giveN-hydroxy-5,6-dimethoxybenzo[b]thiophene-2-carboxamide sodium saltmonohydrate (2.7 g), m.p. 170°-185° C. (decomp.).

EXAMPLE 105,6-Dimethoxy-benzo[b]thiophene-2-carboxaldehyde-amino-iminomethylhydrazone hydrochloride

Aminoguanadinium hydrogen carbonate (2.5 g) was suspended in methanol(35 ml) and the mixture was treated with 5M hydrochloric acid until allthe solid had dissolved. The resultant solution was added to asuspension of 5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde (4.0 g)in ethanol (40 ml) and the mixture was stirred at room temperature for16 hours under an atmosphere of nitrogen. The white suspension was thendiluted with diethyl ether (250 ml) and the white solid was filtered anddried to give5,6-dimethoxybenzo[b]thiophene-2-carboxaldehyde-amino-iminomethylhydrazone hydrochloride (5.3 g). A portion crystallised frommethanol:acetone had m.p. 271°-274° C.

EXAMPLE 11 A. 4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde

Using the procedure described in Example 6A,4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile was convertedinto 4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde, m.p.164°-165° C.

B.4-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde-amino-iminomethylhydrazone hydrochloride

Using the procedure described in Example 10,4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde was convertedinto4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-carboxaldehyde-amino-iminomethylhydrazone hydrochloride, m.p. 255°-265° C. (decomp.).

EXAMPLE 12

In a similar manner as described in Example 6 was prepared:

N-hydroxy-3-(4-chloro-5,6-dimethoxy-benzo[b]thiophene-2-yl)prop-2-eneimidamide;

HCl salt m.p. 192°-198° C. (dec),

and mesylate salt m.p. 148°-151° C.

In a similar manner as described in Example 2 were prepared thefollowing compounds all being substituted derivatives of the basicmolecule:

N-hydroxy-benzo(b)thiophene-2-carboximidamide: ##STR16## viz.3-methyl-5,6-dimethoxy; HCl salt: m.p. 226°-232° C. (dec.);

5,6-dichloro; HCl salt: m.p. 199°-215° C. (dec.);

6,7-dichloro; HCl salt: m.p. 187°-190° C.;

4,7-dichloro-5,6-dimethoxy; HCl salt: m.p. 172°-196° C. (dec.);

7-chloro-5,6-dimethoxy; HCl salt; m.p. 166°-184° C. (dec.);

5-hydroxy-6-methoxy; HCl salt: m.p. 206°-207° C. (dec.);

6-hydroxy-5-methoxy; HCl salt: m.p. 219°-220° C. (dec.);

4-chloro-5-hydroxy-6-methoxy; HCl salt: m.p. 190° C. (dec.);

4,7-dimethoxy; HCl salt: m.p. 158°-178° C. (dec.);

4,5-dimethoxy; HCl salt: m.p. 173°-198° C. (dec);

4-chloro-5-ethoxy-6-methoxy; HCl salt: m.p. 149°-166° C. (dec.);

5,7-dimethoxy; HCl salt: m.p. 190°-194° C. (dec);

6-chloro-5,7-dimethoxy; HCl salt m.p. 212°-215° C. dec;

5-butoxy-4-chloro-6-methoxy; HCl salt 157°-166° C. dec;

5-ethoxy-6-methoxy; HCl salt: m.p. 208°-212° C. dec;

4-chloro-5,6-dihydroxy; HCl salt: m.p. 230° C. dec;

5,6-dimethoxy-4-nitro; mesylate salt 236°-237° C. dec;

5,6-dimethoxy-7-nitro; mesylate salt 214°-216° C. dec;

4-chloro-5,6-dimethoxy; mesylate salt 204°-210° C. dec;

4-amino-5,6-dimethoxy; HCl salt m.p. 193°-195° (dec.).

EXAMPLE 13 5,6-Dimethoxy-benzothiazole-2-carboxamide

1. A solution of potassium hydroxide (30 g) in ethanol (200 ml) wassaturated with dry hydrogen sulphide. The solution was diluted with asolution of potassium hydroxide (30 g) in ethanol (200 ml) and stirredunder nitrogen whilst cooled with an ice/water bath. To this was addeddropwise, a solution of trichloroacetamide (37 g) in ethanol (200 ml)and the red mixture was stirred under nitrogen at room temperature for10 minutes. To this was added a solution of chloroacetic acid (32 g) inwater (200 ml) which had been first neutralised with potassiumcarbonate. The resulting red mixture was stirred vigorously for 10 min.,allowed to stand for 30 min. and the inorganic salt was removed byfiltration. The filtrate (a solution ofcarbamoyl-thiocarbonyl-thioacetic acid) was used without delay forfurther conversion.

2. The solution of carbamoyl-thiocarbonyl thioacetic acid prepared abovewas added to a solution of 3,4-dimethoxy-aniline (20 g) in ethanol (100ml) and water (100 ml). The mixture was allowed to stand in a sealedvessel for 2 hr. The ethanol was evaporated under reduced pressure untilcrystallisation occurred. The product was collected by filtration,washed with cold ethanol, and dried to giveN-(carbamoyl-thiocarbonyl-)-3,4-dimethoxyaniline (14.13 g); m.p.149°-151° C.

3. A solution of N-(carbamoyl-thiocarbonyl-)-3,4-dimethoxy-aniline (14g) in 12% aqueous potassium hydroxide solution (1.26 l) was added slowlyto a stirred solution of potassium ferricyanide (251.5 g) in water (560ml) cooled to 10° C. The thick, yellow precipitate formed was stirredfor 30 min., collected by filtration, washed with water, and dried.Crystallisation from dichloromethane/ethanol gave5,6-dimethoxy-benzothiazole-2-carboxamide (11.98 g); m.p. 211°-212° C.

EXAMPLE 14 N-Hydroxy-5,6-dimethoxy-benzothiazole-2-carboximidamidehydrochloride

Using the procedure described in Example 2A,5,6-dimethoxy-benzothazole-2-carboxamide was converted to5,6-dimethoxy-benzothiazole-2-carbonitrile, m.p. 176°-177° C.

In an analogous manner as described in Example 2B,5,6-dimethoxy-benzothiazole-2-carbonitrile was converted toN-hydroxy-5,6-dimethoxy-benzothiazole-2-carboximidamide hydrochloride;m.p. 230°-232° C. and then converted into its hydrochloride, m.p.205°-208° C. ##STR17##

We claim:
 1. A compound of the formulawherein each R₁ is indpendentlyC₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halogen, NO₂, CF₃ or --NR₅ R₆, orwherein m is at least two then two R₁ groups together may be a methylenedioxy group, m is 1 to 4, n is 0, 1 or 2, R₃ is a member selected fromthe group consisting of ##STR18## and each of R₄, R₅ and R₆ isindependently hydrogen or C₁₋₆ alkyl, or a pharmaceutically acceptablesalt thereof.
 2. A compound of claim 1, wherein m is greater than oneand at least two of R₁ is alkoxy or hydroxy.
 3. A compound of claim 1wherein m is two and the two R1 groups are methylene dioxy.
 4. Acompound of claim 2 wherein each R₁ is methoxy.
 5. A compound of claim 2wherein one R₁ is methoxy and the other R₁ is hydroxy.
 6. The compoundaccording to claim 1:N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide orpharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1:4-chloro-N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide ora pharmaceutically acceptable salt thereof.